Phosphonate nucleotide derivatives

ABSTRACT

A compound represented by the following general formula (I) which has an antiviral activity:                    
     wherein R 1  represents hydrogen atom, C 1 -C 6  alkyl group, or C 7 -C 10  aralkyl group; R 2  represents C 1 -C 6  alkyl group, C 7 -C 10  aralkyl group, or phenyl group; R 3  and R 4  independently represent hydrogen atom, C 1 -C 6  alkyl group, acyloxymethyl group, acylthioethyl group, or ethyl gorup substituted with at least one halogen atom; R 5  represents hydrogen atom, C 1 -C 4  alkyl gorup, C 1 -C 4  hydroxyalkyl group, C 1 -C 4  alkyl group substituted with at least one halogen atom; and X represents carbon atom or nitrogen atom.

This application is a 371 of International Application No. PCT/JP96/01631 filed Jun. 14, 1996.

1. Technical Field

The present invention relates to novel phosphonate nucleotide derivatives. More specifically, it relates to novel phosphonate nucleotide derivatives which have antiviral activity and are useful as active ingredients of medicaments.

2. Background Art

Viral infectious diseases are recognized as a major medical problem, and to achieve therapeutic treatment of these diseases, it has been attempted to develop medicaments having antiviral activity and not exhibiting growth inhibitory activity on healthy cellular systems. For example, a class of phosphonate nucleotides has been intensively studied recently as compounds having selective toxicity against viruses. More specifically, it has been reported that 9-(2-phosphonylmethoxy)ethyladenine (PMEA), 9-(2-phosphonylmethoxy)ethyl-2,6-diaminopurine (PMDAP) and the like are effective against herpes simplex viruses type-1 and type-2 (HSV-1 and HSV-2), human immunodeficiency virus (HIV), and human hepatitis B virus (HBV) (Yokota et al., Antimicrob. Agents Chemother., 35, 394 (1991); and Votruba et al. Mol. Pharmacol., 32, 524 (1987)).

However, these known phosphonate nucleotides may possibly have toxicity to a living body, including myeloid cell growth inhibition as a typical example, and mutagenicity, and their problems have been pointed out from a viewpoint of safety (Antiviral Research, 16, 77 (1991)). In addition, these compounds have insufficient oral absorbability (DeClercq et al., Antimicrob. Agents Chemother., 33, 185 (1989)), and accordingly, parenteral administration such as intravenous injection or intramuscular injection is unavoidably applied in order to obtain an essential blood concentration for exhibiting efficacy. Therapeutic treatment by parenteral administration cannot be applied to patients other than inpatients, and such method is undesired for treatment of diseases such as AIDS or hepatitis B virus infectious disease which require long-term therapy.

On the other hand, the inventors of the present invention found that specific ester derivatives of phosphonate nucleotides have antiviral activity and high oral absorbability (European Patent Publication No. 632,048). Howver, the derivatives have not yet been clinically developed.

DISCLOSURE OF THE INVENTION

The inventors of the present invention conducted intensive researches to solve the foregoing problems, and a result, they found that a specific class of phosphonate nucleotides having novel chemical structures have higher antiviral activity compared to compounds already reported, and that they are safer to a living body and have high oral absorbability. The present invention was achieved on the basis of these findings.

The present invention thus provides phosphonate nucleotide derivatives represented by the following general formula (I) and salts thereof, and hydrates and solvates thereof:

In the above formula, R¹ represents hydrogen atom, a C₁-C₆ alkyl group, or a C₇-C₁₀ aralkyl group; R² represents a C₁-C₆ alkyl group, a C₇-C₁₀ aralkyl group, or phenyl group, R³ and R⁴ each independently represent hydrogen atom, a C₁-C₆ alkyl group, an acyloxymethyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms; R⁵ represents hydrogen atom, a C₁-C₄ alkyl group, a C₁-C₄ hydroxyalkyl group, or a C₁-C₄ alkyl group substituted with one or more halogen atoms; and X represents —CH— or nitrogen atom.

According to further embodiments of the present invention, there are provided medicaments comprising the above substances; pharmaceutical compositions and antiviral agents comprising the above substances as an active ingredient. In addition, there are also provided uses of the above substances for the manufacture of pharmaceutical compositions having antiviral activity, and methods for treatment of viral infectious diseases comprising the step of administering a therapeutically effective amount of the above substance to a patient.

BEST MODE FOR CARRYING OUT THE INVENTION

In the phosphonate nucleotide derivatives of the above general formula (I), examples of the C₁-C₆ alkyl group represented by R¹, R², R³, and R⁴ include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group or the like.

Examples of the C₇-C₁₀ aralkyl group represented by R¹ and R² include, for example, benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group or the like.

In particular, hydrogen atom and a C₁-C₄ alkyl group are preferred as R¹, and a C₁-C₄ alkyl group, benzyl group, and phenyl group are preferred as R². As R², a C₁-C₄ alkyl group and phenyl group are particularly preferred. The C₁-C₄ alkyl group represented by R⁵ may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group or the like.

The acyloxymethyl group represented by R³ and R⁴ may be, for example, acetyloxymethyl group, propionyloxymethyl group, butyryloxymethyl group, isobutyryloxymethyl group, valeryloxymethyl group, isovaleryloxymethyl group, pivaloyloxymethyl group or the like.

The acylthioethyl group represented by R³ and R⁴ may be, for example, acetylthioethyl group, propionylthioethyl group, butyrylthioethyl group, isobutyrylthioethyl group, valerylthioethyl group, isovalerylthioethyl group, pivaloylthioethyl group or the like.

In the ethyl group substituted with one or more halogen atoms represented by R³ and R⁴, the halogen atom includes fluorine atom, chlorine atom, bromine atom, and iodine atom. Examples of the ethyl group substituted with one or more halogen atoms include 1-fluoroethyl group, 2-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group, 2-bromoethyl group, 2,2-difluoroethyl group, 2,2-dichloroethyl group, 2,2-dibromoethyl group, 2,2,2-trifluoroethyl group, 2,2,2-trichloroethyl group, 2,2,2-tribromoethyl group and the like. In particular, ethyl groups substituted at the 2-position are preferred, and fluorine atom is preferred as the halogen atom.

As R³ and R⁴, a C₁-C₆ alkyl group or an ethyl group substituted with one or more halogen atoms are preferred, and 2,2,2-trifluoroethyl group is particularly preferred.

Examples of the C₁-C₄ hydroxyalkyl group represented by R⁵ include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group and the like.

In the C₁-C₄ alkyl group substituted with one or more halogen atoms represented by R⁵, examples of the halogen atom include fluorine atom and chlorine atoms or the like, and examples of the C₁-C₄ alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group or the like. Examples of the C₁-C₄ alkyl group substituted with one or more halogen atoms include fluoromethyl group, difluoromethyl group, trifluoromethyl group, fluoroethyl group, chloroethyl group, fluoropropyl group, chloropropyl group, fluorobutyl group, chlorobutyl group and the like.

Hydrogen atom or a C₁-C₄ alkyl group is preferred as R⁵.

The compounds of the present invention are characterized in that they have higher antiviral activity compared to a compound disclosed in European Patent Publication No. 632,048, which is derived by the replacement of the amino group at the 6-position of purine ring with a substituted amino group, and that they are safer to living bodies and can achieve higher oral absorbability. Among the compounds of the present invention, its has been found that those having phenyl group as R² are characterized to have lower toxicity compared to those having an alkyl group or aralkyl group as R², and those having an alkyl group as R⁵ are characterized to have lower toxicity compared to those having hydrogen atom, hydroxyalkyl group, or an alkyl group substituted with one or more halogen atoms as R⁵.

Examples of particularly preferred compounds among the compounds of the present invention include:

2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-(phenylamino)purine;

2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-(N-methylphenylamino)purine;

2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-(phenylamino)purine;

2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-(N-methylphenylamino)purine; and

2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-(dimethylamino)purine.

The phosphonate nucleotide derivatives of the present invention represented by the above general formula (I) may form pharmacologically and pharmaceutically acceptable salts. Specific examples of such salts include, when they have an acidic group, a metal salt such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, an ammonium salt such as ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, and dicyclohexylammonium salt and other. When a basic group exists, they can form mineral acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, or organic acid salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, propionate, tartrate, fumarate, maleate, malate, oxalate, succinate, citrate, benzoate, mandelate, cinnamate, and lactate.

The phosphonate nucleotide derivatives of the present invention represented by the above general formula (I) and salts thereof may exist in the form of a hydrate or a solvate. Examples of solvents which can form the solvate include methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like. It should be understood that the compounds represented by the general formula (I) as a free form and salts thereof, and their hydrates and solvates fall within the scope of the present invention.

Specific examples of the compound of the present invention are shown in Table 1 set out below. In the table, “Me” represents methyl group, “Et” represents ethyl group, “n-Pr” represents n-propyl group, “i-Pr” represents isopropyl group, “n-Bu” represents n-butyl group, “t-Bu” represents tertiary butyl group, and “Ph” represents phenyl group.

TABLE 1 Com- pound No. R¹ R² R³ R⁴ R⁵ X  1 H Me CF₃CH₂— CF₃CH₂— H C  2 H Et CF₃CH₂— CF₃CH₂— H C  3 H n-Pr CF₃CH₂— CF₃CH₂— H C  4 H i-Pr CF₃CH₂— CF₃CH₂— H C  5 H n-Bu CF₃CH₂— CF₃CH₂— H C  6 H Me CF₃CH₂— CF₃CH₂— H N  7 H Et- CF₃CH₂— CF₃CH₂— H N  8 H n-Pr CF₃CH₂— CF₃CH₂— H N  9 H i-Pr CF₃CH₂— CF₃CH₂— H N  10 H n-Bu CF₃CH₂— CF₃CH₂— H N  11 Me Me CF₃CH₂— CF₃CH₂— H C  12 Me Et CF₃CH₂— CF₃CH₂— H C  13 Me n-Pr CF₃CH₂— CF₃CH₂— H C  14 Me i-Pr CF₃CH₂— CF₃CH₂— H C  15 Me n-Bu CF₃CH₂— CF₃CH₂— H C  16 Et Et CF₃CH₂— CF₃CH₂— H C  17 Et n-Pr CF₃CH₂— CF₃CH₂— H C  18 Et i-Pr CF₃CH₂— CF₃CH₂— H C  19 Et n-Bu CF₃CH₂— CF₃CH₂— H C  20 n-Pr n-Pr CF₃CH₂— CF₃CH₂— H C  21 Me Me CF₃CH₂— CF₃CH₂— H N  22 Me Et CF₃CH₂— CF₃CH₂— H N  23 Me n-Pr CF₃CH₂— CF₃CH₂— H N  24 Me i-Pr CF₃CH₂— CF₃CH₂— H N  25 Me n-Bu CF₃CH₂— CF₃CH₂— H N  26 Et Et CF₃CH₂— CF₃CH₂— H N  27 Et n-Pr CF₃CH₂— CF₃CH₂— H N  28 Et i-Pr CF₃CH₂— CF₃CH₂— H N  29 Et n-Bu CF₃CH₂— CF₃CH₂— H N  30 n-Pr n-Pr CF₃CH₂— CF₃CH₂— H N  31 H Me Me CF₃CH₂— H C  32 H Et Me CF₃CH₂— H C  33 H n-Pr Me CF₃CH₂— H C  34 H i-Pr Me CF₃CH₂— H C  35 H n-Bu Me CF₃CH₂— H C  36 H Me Me CF₃CH₂— H N  37 H Et Me CF₃CH₂— H N  38 H n-Pr Me CF₃CH₂— H N  39 H i-Pr Me CF₃CH₂— H N  40 H n-Bu Me CF₃CH₂— H N  41 Me Me Me CF₃CH₂— H C  42 Me Et Me CF₃CH₂— H C  43 Me n-Pr Me CF₃CH₂— H C  44 Me i-Pr Me CF₃CH₂— H C  45 Me n-Bu Me CF₃CH₂— H C  46 Et Et Me CF₃CH₂— H C  47 Et n-Pr Me CF₃CH₂— H C  48 Et i-Pr Me CF₃CH₂— H C  49 Et n-Bu Me CF₃CH₂— H C  50 n-Pr n-Pr Me CF₃CH₂— H C  51 Me Me Me CF₃CH₂— H N  52 Me Et Me CF₃CH₂— H N  53 Me n-Pr Me CF₃CH₂— H N  54 Me i-Pr Me CF₃CH₂— H N  55 Me n-Bu Me CF₃CH₂— H N  56 Et Et Me CF₃CH₂— H N  57 Et n-Pr Me CF₃CH₂— H N  58 Et i-Pr Me CF₃CH₂— H N  59 Et n-Bu Me CF₃CH₂— H N  60 n-Pr n-Pr Me CF₃CH₂— H N  61 H Me CF₃CH₂— H H C  62 H Et CF₃CH₂— H H C  63 H n-Pr CF₃CH₂— H H C  64 H i-Pr CF₃CH₂— H H C  65 H n-Bu CF₃CH₂— H H C  66 H Me CF₃CH₂— H H N  67 H Et CF₃CH₂— H H N  68 H n-Pr CF₃CH₂— H H N  69 H i-Pr CF₃CH₂— H H N  70 H n-Bu CF₃CH₂— H H N  71 Me Me CF₃CH₂— H H C  72 Me Et CF₃CH₂— H H C  73 Me n-Pr CF₃CH₂— H H C  74 Me i-Pr CF₃CH₂— H H C  75 Me n-Bu CF₃CH₂— H H C  76 Et Et CF₃CH₂— H H C  77 Et n-Pr CF₃CH₂— H H C  78 Et i-Pr CF₃CH₂— H H C  79 Et n-Bu CF₃CH₂— H H C  80 n-Pr n-Pr CF₃CH₂— H H C  81 Me Me CF₃CH₂— H H N  82 Me Et CF₃CH₂— H H N  83 Me n-Pr CF₃CH₂— H H N  84 Me i-Pr CF₃CH₂— H H N  85 Me n-Bu CF₃CH₂— H H N  86 Et Et CF₃CH₂— H H N  87 Et n-Pr CF₃CH₂— H H N  88 Et i-Pr CF₃CH₂— H H N  89 Et n-Bu CF₃CH₂— H H N  90 n-Pr n-Pr CF₃CH₂— H H N  91 H Me H H H C  92 H Et H H H C  93 H n-Pr H H H C  94 H i-Pr H H H C  95 H n-Bu H H H C  96 H Me H H H N  97 H Et H H H N  98 H n-Pr H H H N  99 H i-Pr H w H N 100 H n-Bu H H H N 101 Me Me H H H C 102 Me Et H H H C 103 Me n-Pr H H H C 104 Me i-Pr H H H C 105 Me n-Bu H H H C 106 Et Et H H H C 107 Et n-Pr H H H C 108 Et i-Pr H H H C 109 Et n-Bu H H H C 110 n-Pr n-Pr H H H C 111 Me Me H H H N 112 Me Et H H H N 113 Me n-Pr H H H N 114 Me i-Pr H H H N 115 Me n-Bu H H H N 116 Et Et H H H N 117 Et n-Pr H H H N 118 Et i-Pr H H H N 119 Et n-Bu H H H N 120 n-Pr n-Pr H H H N 121 H —CH₂-Ph CF₃CH₂— CF₃CH₂— H C 122 H —CH₂-Ph H CF₃CH₂— H C 123 H —CH₂-Ph Me CF₃CH₂— H C 124 H —CH₂-Ph H H H C 125 H —CH₂-Ph CF₃CH₂— CF₃CH₂— H N 126 H —CH₂-Ph Me CF₃CH₂— H N 127 H —CH₂-Ph H CF₃CH₂— H N 128 H —CH₂-Ph H H H N 129 Me —CH₂-Ph CF₃CH₂— CF₃CH₂— H C 130 Me —CH₂-Ph Me CF₃CH₂— H C 131 Me —CH₂-Ph H CF₃CH₂— H C 132 Me —CH₂-Ph H H H C 133 Me —CH₂-Ph CF₃CH₂— CF₃CH₂— H N 134 Me —CH₂-Ph Me CF₃CH₂— H N 135 Me —CH₂-Ph H CF₃CH₂— H N 136 Me —CH₂-Ph H H H N 137 H Me CF₃CH₂— CF₃CH₂— —CH₂F C 138 H Et CF₃CH₂— CF₃CH₂— —CH₂F C 139 H n-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 140 H i-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 141 H n-Bu CF₃CH₂— CF₃CH₂— —CH₂F C 142 H Me CF₃CH₂— CF₃CH₂— —CH₂F N 143 H Et CF₃CH₂— CF₃CH₂— —CH₂F N 144 H n-Pr CF₃CH₂— CF₃CH₂— —CH₂F N 145 H i-Pr CF₃CH₂— CF₃CH₂— —CH₂F N 146 H n-Bu CF₃CH₂— CF₃CH₂— —CH₂F N 147 Me Me CF₃CH₂— CF₃CH₂— —CH₂F C 148 Me Et CF₃CH₂— CF₃CH₂— —CH₂F C 149 Me n-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 150 Me i-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 151 Me n-Bu CF₃CH₂— CF₃CH₂— —CH₂F C 152 Et Et CF₃CH₂— CF₃CH₂— —CH₂F C 153 Et n-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 154 Et i-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 155 Et n-Bu CF₃CH₂— CF₃CH₂— —CH₂F C 156 n-Pr n-Pr CF₃CH₂— CF₃CH₂— —CH₂F C 157 Me Me CF₃CH₂— CF₃CH₂— —CH₂F N 158 Me Et CF₃CH₂— CF₃CH₂— —CH₂F N 159 Me n-Pr CF₃CH₂— CF₃CH₂— —CH₂F N 160 Me i-Pr CF₃CH₂— CF₃CH₂— —CH₂F N 161 Me n-Bu CF₃CH₂— CF₃CH₂— —CH₂F N 162 Et Et CF₃CH₂— CF₃CH₂— —CH₂F N 163 Et n-Pr CF₃CH₂— CF₃CH₂— —CH₂F N 164 Et i-Pr CF₃CH₂— CF₃CH₂— CH2F N 165 Et n-Bu CF₃CH₂— CF₃CH₂— —CH₂F N 166 n-Pr n-Pr CF₃CH₂— CF₃CH₂— —CH₂F N 167 H Me Me CF₃CH₂— —CH₂F C 168 H Et Me CF₃CH₂— —CH₂F C 169 H n-Pr Me CF₃CH₂— —CH₂F C 170 H i-Pr Me CF₃CH₂— —CH₂F C 171 H n-Bu Me CF₃CH₂— —CH₂F C 172 H Me Me CF₃CH₂— —CH₂F N 173 H Et Me CF₃CH₂— —CH₂F N 174 H n-Pr Me CF₃CH₂— —CH₂F N 175 H i-Pr Me CF₃CH₂— —CH₂F N 176 H n-Bu Me CF₃CH₂— —CH₂F N 177 Me Me Me CF₃CH₂— —CH₂F C 178 Me Et Me CF₃CH₂— —CH₂F C 179 Me n-Pr Me CF₃CH₂— —CH₂F C 180 Me i-Pr Me CF₃CH₂— —CH₂F C 181 Me n-Bu Me CF₃CH₂— —CH₂F C 182 Et Et Me CF₃CH₂— —CH₂F C 183 Et n-Pr Me CF₃CH₂— —CH₂F C 184 Et i-Pr Me CF₃CH₂— —CH₂F C 185 Et n-Bu Me CF₃CH₂— —CH₂F C 186 n-Pr n-Pr Me CF₃CH₂— —CH₂F C 187 Me Me Me CF₃CH₂— —CH₂F N 188 Me Et Me CF₃CH₂— —CH₂F N 189 Me n-Pr Me CF₃CH₂— —CH₂F N 190 Me i-Pr Me CF₃CH₂— —CH₂F N 191 Me n-Bu Me CF₃CH₂— —CH₂F N 192 Et Et Me CF₃CH₂— —CH₂F N 193 Et n-Pr Me CF₃CH₂— —CH₂F N 194 Et i-Pr Me CF₃CH₂— —CH₂F N 195 Et n-Bu Me CF₃CH₂— —CH₂F N 196 n-Pr n-Pr Me CF₃CH₂— —CH₂F N 197 H Me CF₃CH₂— H —CH₂F C 198 H Et CF₃CH₂— H —CH₂F C 199 H n-Pr CF₃CH₂— H —CH₂F C 200 H i-Pr CF₃CH₂— H —CH₂F C 201 H n-Bu CF₃CH₂— H —CH₂F C 202 H Me CF₃CH₂— H —CH₂F N 203 H Et CF₃CH₂— H —CH₂F N 204 H n-Pr CF₃CH₂— H —CH₂F N 205 H i-Pr CF₃CH₂— H —CH₂F N 206 H n-Bu CF₃CH₂— H —CH₂F N 207 Me Me CF₃CH₂— H —CH₂F C 208 Me Et CF₃CH₂— H —CH₂F C 209 Me n-Pr CF₃CH₂— H —CH₂F C 210 Me i-Pr CF₃CH₂— H —CH₂F C 211 Me n-Bu CF₃CH₂— H —CH₂F C 212 Et Et CF₃CH₂— H —CH₂F C 213 Et n-Pr CF₃CH₂— H —CH₂F C 214 Et i-Pr CF₃CH₂— H —CH₂F C 215 Et n-Bu CF₃CH₂— H —CH₂F C 216 n-Pr n-Pr CF₃CH₂— H —CH₂F C 217 Me Me CF₃CH₂— H —CH₂F N 218 Me Et CF₃CH₂— H —CH₂F N 219 Me n-Pr CF₃CH₂— H —CH₂F N 220 Me i-Pr CF₃CH₂— H —CH₂F N 221 Me n-Bu CF₃CH₂— H —CH₂F N 222 Et Et CF₃CH₂— H —CH₂F N 223 Et n-Pr CF₃CH₂— H —CH₂F N 224 Et i-Pr CF₃CH₂— H —CH₂F N 225 Et n-Bu CF₃CH₂— H —CH₂F N 226 n-Pr n-Pr CF₃CH₂— H —CH₂F N 227 H Me H H —CH₂F C 228 H Et H H —CH₂F C 229 H n-Pr H H —CH₂F C 230 H i-Pr H H —CH₂F C 231 H n-Bu H H —CH₂F C 232 H Me H H —CH₂F N 233 H Et H H —CH₂F N 234 H n-Pr H H —CH₂F N 235 H i-Pr H H —CH₂F N 236 H n-Bu H H —CH₂F N 237 Me Me H H —CH₂F C 238 Me Et H H —CH₂F C 239 Me n-Pr H H —CH₂F C 240 Me i-Pr H H —CH₂F C 241 Me n-Bu H H —CH₂F C 242 Et Et H H —CH₂F C 243 Et n-Pr H H —CH₂F C 244 Et i-Pr H H —CH₂F C 245 Et n-Bu H H —CH₂F C 246 n-Pr n-Pr H H —CH₂F C 247 Me Me H H —CH₂F N 248 Me Et H H —CH₂F N 249 Me n-Pr H H —CH₂F N 250 Me i-Pr H H —CH₂F N 251 Me n-Bu H H —CH₂F N 252 Et Et H H —CH₂F N 253 Et n-Pr H H —CH₂F N 254 Et i-Pr H H —CH₂F N 255 Et n-Bu H H —CH₂F N 256 n-Pr n-Pr H H —CH₂F N 257 H Ph CF₃CH₂— CF₃CH₂— —CH₂F C 258 H Ph H CF₃CH₂— —CH₂F C 259 H Ph Me CF₃CH₂— —CH₂F C 260 H Ph H H —CH₂F C 261 H Ph CF₃CH₂— CF₃CH₂— —CH₂F N 262 H Ph Me CF₃CH₂— —CH₂F N 263 H Ph H CF₃CH₂— —CH₂F N 264 H Ph H H —CH₂F N 265 Me Ph CF₃CH₂— CF₃CH₂— —CH₂F C 266 Me Ph Me CF₃CH₂— —CH₂F C 267 Me Ph H CF₃CH₂— —CH₂F C 268 Me Ph H H —CH₂F C 269 Me Ph CF₃CH₂— CF₃CH₂— —CH₂F N 270 Me Ph Me CF₃CH₂— —CH₂F N 271 Me Ph H CF₃CH₂— —CH₂F N 272 Me Ph H H —CH₂F N 273 H Me CF₃CH₂— CF₃CH₂— —CH₂OH C 274 H Et CF₃CH₂— CF₃CH₂— —CH₂OH C 275 H n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 276 H i-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 277 H n-Bu CF₃CH₂— CF₃CH₂— —CH₂OH C 278 H Me CF₃CH₂— CF₃CH₂— —CH₂OH N 279 H Et CF₃CH₂— CF₃CH₂— —CH₂OH N 280 H n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 281 H i-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 282 H n-Bu CF₃CH₂— CF₃CH₂— —CH₂OH N 283 Me Me CF₃CH₂— CF₃CH₂— —CH₂OH C 284 Me Et CF₃CH₂— CF₃CH₂— —CH₂OH C 285 Me n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 286 Me i-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 287 Me n-Bu CF₃CH₂— CF₃CH₂— —CH₂OH C 288 Et Et CF₃CH₂— CF₃CH₂— —CH₂OH C 289 Et n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 290 Et i-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 291 Et n-Bu CF₃CH₂— CF₃CH₂— —CH₂OH C 292 n-Pr n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH C 293 Me Me CF₃CH₂— CF₃CH₂— —CH₂OH N 294 Me Et CF₃CH₂— CF₃CH₂— —CH₂OH N 295 Me n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 296 Me i-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 297 Me n-Bu CF₃CH₂— CF₃CH₂— —CH₂OH N 298 Et Et CF₃CH₂— CF₃CH₂— —CH₂OH N 299 Et n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 300 Et i-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 301 Et n-Bu CF₃CH₂— CF₃CH₂— —CH₂OH N 302 n-Pr n-Pr CF₃CH₂— CF₃CH₂— —CH₂OH N 303 H Me Me CF₃CH₂— —CH₂OH C 304 H Et Me CF₃CH₂— —CH₂OH C 305 H n-Pr Me CF₃CH₂— —CH₂OH C 306 H i-Pr Me CF₃CH₂— —CH₂OH C 307 H n-Bu Me CF₃CH₂— —CH₂OH C 308 H Me Me CF₃CH₂— —CH₂OH N 309 H Et Me CF₃CH₂— —CH₂OH N 310 H n-Pr Me CF₃CH₂— —CH₂OH N 311 H i-Pr Me CF₃CH₂— —CH₂OH N 312 H n-Bu Me CF₃CH₂— —CH₂OH N 313 Me Me Me CF₃CH₂— —CH₂OH C 314 Me Et Me CF₃CH₂— —CH₂OH C 315 Me n-Pr Me CF₃CH₂— —CH₂OH C 316 Me i-Pr Me CF₃CH₂— —CH₂OH C 317 Me n-Bu Me CF₃CH₂— —CH₂OH C 318 Et Et Me CF₃CH₂— —CH₂OH C 319 Et n-Pr Me CF₃CH₂— —CH₂OH C 320 Et i-Pr Me CF₃CH₂— —CH₂OH C 321 Et n-Bu Me CF₃CH₂— —CH₂OH C 322 n-Pr n-Pr Me CF₃CH₂— —CH₂OH C 323 Me Me Me CF₃CH₂— —CH₂OH N 324 Me Et Me CF₃CH₂— —CH₂OH N 325 Me n-Pr Me CF₃CH₂— —CH₂OH N 326 Me i-Pr Me CF₃CH₂— —CH₂OH N 327 Me n-Bu Me CF₃CH₂— —CH₂OH N 328 Et Et Me CF₃CH₂— —CH₂OH N 329 Et n-Pr Me CF₃CH₂— —CH₂OH N 330 Et i-Pr Me CF₃CH₂— —CH₂OH N 331 Et n-Bu Me CF₃CH₂— —CH₂OH N 332 n-Pr n-Pr Me CF₃CH₂— —CH₂OH N 333 H Me CF₃CH₂— H —CH₂OH C 334 H Et CF₃CH₂— H —CH₂OH C 335 H n-Pr CF₃CH₂— H —CH₂OH C 336 H i-Pr CF₃CH₂— H —CH₂OH C 337 H n-Bu CF₃CH₂— H —CH₂OH C 338 H Me CF₃CH₂— H —CH₂OH N 339 H Et CF₃CH₂— H —CH₂OH N 340 H n-Pr CF₃CH₂— H —CH₂OH N 341 H i-Pr CF₃CH₂— H —CH₂OH N 342 H n-Bu CF₃CH₂— H —CH₂OH N 343 Me Me CF₃CH₂— H —CH₂OH C 344 Me Et CF₃CH₂— H —CH₂OH C 345 Me n-Pr CF₃CH₂— H —CH₂OH C 346 Me i-Pr CF₃CH₂— H —CH₂OH C 347 Me n-Bu CF₃CH₂— H —CH₂OH C 348 Et Et CF₃CH₂— H —CH₂OH C 349 Et n-Pr CF₃CH₂— H —CH₂OH C 350 Et i-Pr CF₃CH₂— H —CH₂OH C 351 Et n-Bu CF₃CH₂— H —CH₂OH C 352 n-Pr n-Pr CF₃CH₂— H —CH₂OH C 353 Me Me CF₃CH₂— H —CH₂OH N 354 Me Et CF₃CH₂— H —CH₂OH N 355 Me n-Pr CF₃CH₂— H —CH₂OH N 356 Me i-Pr CF₃CH₂— H —CH₂OH N 357 Me n-Bu CF₃CH₂— H —CH₂OH N 358 Et Et CF₃CH₂— H —CH₂OH N 359 Et n-Pr CF₃CH₂— H —CH₂OH N 360 Et i-Pr CF₃CH₂— H —CH₂OH N 361 Et n-Bu CF₃CH₂— H —CH₂OH N 362 n-Pr n-Pr CF₃CH₂— H —CH₂OH N 363 H Me H H —CH₂OH C 364 H Et H H —CH₂OH C 365 H n-Pr H H —CH₂OH C 366 H i-Pr H H —CH₂OH C 367 H n-Bu H H —CH₂OH C 368 H Me H H —CH₂OH N 369 H Et H H —CH₂OH N 370 H n-Pr H H —CH₂OH N 371 H i-Pr H H —CH₂OH N 372 H n-Bu H H —CH₂OH N 373 Me Me H H —CH₂OH C 374 Me Et H H —CH₂OH C 375 Me n-Pr H H —CH₂OH C 376 Me i-Pr H H —CH₂OH C 377 Me n-Bu H H —CH₂OH C 378 Et Et H H —CH₂OH C 379 Et n-Pr H H —CH₂OH C 380 Et i-Pr H H —CH₂OH C 381 Et n-Bu H H —CH₂OH C 382 n-Pr n-Pr H H —CH₂OH C 383 Me Me H H —CH₂OH N 384 Me Et H H —CH₂OH N 385 Me n-Pr H H —CH₂OH N 386 Me i-Pr H H —CH₂OH N 387 Me n-Bu H H —CH₂OH N 388 Et Et H H —CH₂OH N 389 Et n-Pr H H —CH₂OH N 390 Et i-Pr H H —CH₂OH N 391 Et n-Bu H H —CH₂OH N 392 n-Pr n-Pr H H —CH₂OH N 393 H Ph CF₃CH₂— CF₃CH₂— —CH₂OH C 394 H Ph H CF₃CH₂— —CH₂OH C 395 H Ph Me CF₃CH₂— —CH₂OH C 396 H Ph H H —CH₂OH C 397 H Ph CF₃CH₂— CF₃CH₂— —CH₂OH N 398 H Ph Me CF₃CH₂— —CH₂OH N 399 H Ph H CF₃CH₂— —CH₂OH N 400 H Ph H H —CH₂OH N 401 Me Ph CF₃CH₂— CF₃CH₂— —CH₂OH C 402 Me Ph Me CF₃CH₂— —CH₂OH C 403 Me Ph H CF₃CH₂— —CH₂OH C 404 Me Ph H H —CH₂OH C 405 Me Ph CF₃CH₂— CF₃CH₂— —CH₂OH N 406 Me Ph Me CF₃CH₂— —CH₂OH N 407 Me Ph H CF₃CH₂— —CH₂OH N 408 Me Ph H H —CH₂OH N 409 H Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 410 H Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 411 H n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 412 H i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 413 H n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 414 H Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 415 H Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 416 H n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 417 H i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 418 H n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 419 Me Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 420 Me Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 421 Me n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 422 Me i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 423 Me n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 424 Et Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 425 Et n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 426 Et i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 427 Et n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 428 n-Pr n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 429 Me Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 430 Me Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 431 Me n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 432 Me i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 433 Me n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 434 Et Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 435 Et n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 436 Et i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 437 Et n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 438 n-Pr n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 439 H Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 440 H Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 441 H n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 442 H i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 443 H n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 444 H Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 445 H Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 446 H n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 447 H i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 448 H n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 449 Me Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 450 Me Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 451 Me n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 452 Me i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 453 Me n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 454 Et Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 455 Et n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 456 Et i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 457 Et n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 458 n-Pr n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 459 Me Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 460 Me Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 461 Me n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 462 Me i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 463 Me n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 464 Et Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 465 Et n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 466 Et i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 467 Et n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 468 n-Pr n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 469 H Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 470 H Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 471 H n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 472 H i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 473 H n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 474 H Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 475 H Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 476 H n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 477 H i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 478 H n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 479 Me Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 480 Me Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 481 Me n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 482 Me i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 483 Me n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 484 Et Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 485 Et n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 486 Et i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 487 Et n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 488 n-Pr n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 489 Me Me —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 490 Me Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 491 Me n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 492 Me i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 493 Me n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 494 Et Et —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 495 Et n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 496 Et i-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 497 Et n-Bu —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 498 n-Pr n-Pr —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 499 H Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 500 H Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 501 H n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 502 H i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 503 H n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 504 H Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 505 H Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 506 H n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 507 H i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 508 H n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 509 Me Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 510 Me Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 511 Me n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 512 Me i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 513 Me n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 514 Et Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 515 Et n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 516 Et i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 517 Et n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 518 n-Pr n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 519 Me Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 520 Me Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 521 Me n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 522 Me i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 523 Me n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 524 Et Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 525 Et n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 526 Et i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 527 Et n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 528 n-Pr n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 529 H Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 530 H Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 531 H n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 532 H i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 533 H n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 534 H Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 535 H Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 536 H n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 537 H i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 538 H n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 539 Me Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 540 Me Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 541 Me n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 542 Me i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 543 Me n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 544 Et Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 545 Et n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 546 Et i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 547 Et n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 548 n-Pr n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 549 Me Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 550 Me Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 551 Me n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 552 Me i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 553 Me n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 554 Et Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 555 Et n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 556 Et i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 557 Et n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 558 n-Pr n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 559 H Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 560 H Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 561 H n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 562 H i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 563 H n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 564 H Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 565 H Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 566 H n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 567 H i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 568 H n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 569 Me Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 570 Me Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 571 Me n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 572 Me i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 573 Me n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 574 Et Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 575 Et n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 576 Et i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 577 Et n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 578 n-Pr n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 579 Me Me —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 580 Me Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 581 Me n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 582 Me i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 583 Me n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 584 Et Et —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 585 Et n-Pr —CH₂CH₂S—CO-i-Pr CH₂CH₂S—CO-i-Pr —CH₂OH N 586 Et i-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 587 Et n-Bu —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 588 n-Pr n-Pr —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 589 H Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 590 H Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 591 H Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 592 H Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 593 H Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 594 H Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 595 Me Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me C 596 Me Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F C 597 Me Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH C 598 Me Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu Me N 599 Me Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂F N 600 Me Ph —CH₂OCO-t-Bu —CH₂OCO-t-Bu —CH₂OH N 601 H Ph —CH₂CH₂S—CO-i-Pr —CH₂CH9S-CO-i-Pr Me C 602 H Ph —CH₂CH₂S—CO-i-Pr —CH₂CH9S-CO-i-Pr —CH₂F C 603 H Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 604 H Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 605 H Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 606 H Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 607 Me Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me C 608 Me Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F C 609 Me Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH C 610 Me Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr Me N 611 Me Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂F N 612 Me Ph —CH₂CH₂S—CO-i-Pr —CH₂CH₂S—CO-i-Pr —CH₂OH N 613 H Ph CF₃CH₂— CF₃CH₂— H C 614 H Ph H CF₃CH₂— H C 615 H Ph Me CF₃CH₂— H C 616 H Ph H H H C 617 H Ph CF₃CH₂— CF₃CH₂— H N 618 H Ph Me CF₃CH₂— H N 619 H Ph H CF₃CH₂— H N 620 H Ph H H H N 621 Me Ph CF₃CH₂— CF₃CH₂— H C 622 Me Ph Me CF₃CH₂— H C 623 Me Ph H CF₃CH₂— H C 624 Me Ph H H H C 625 Me Ph CF₃CH₂— CF₃CH₂— H N 626 Me Ph Me CF₃CH₂— H N 627 Me Ph H CF₃CH₂— H N 628 Me Ph H H H N 629 H Me CF₃CH₂— CF₃CH₂— Me C 630 H Et CF₃CH₂— CF₃CH₂— Me C 631 H n-Pr CF₃CH₂— CF₃CH₂— Me C 632 H i-Pr CF₃CH₂— CF₃CH₂— Me C 633 H n-Bu CF₃CH₂— CF₃CH₂— Me C 634 H Me CF₃CH₂— CF₃CH₂— Me N 635 H Et CF₃CH₂— CF₃CH₂— Me N 636 H n-Pr CF₃CH₂— CF₃CH₂— Me N 637 H i-Pr CF₃CH₂— CF₃CH₂— Me N 638 H n-Bu CF₃CH₂— CF₃CH₂— Me N 639 Me Me CF₃CH₂— CF₃CH₂— Me C 640 Me Et CF₃CH₂— CF₃CH₂— Me C 641 Me n-Pr CF₃CH₂— CF₃CH₂— Me C 642 Me i-Pr CF₃CH₂— CF₃CH₂— Me C 643 Me n-Bu CF₃CH₂— CF₃CH₂— Me C 644 Et Et CF₃CH₂— CF₃CH₂— Me C 645 Et n-Pr CF₃CH₂— CF₃CH₂— Me C 646 Et i-Pr CF₃CH₂— CF₃CH₂— Me C 647 Et n-Bu CF₃CH₂— CF₃CH₂— Me C 648 n-Pr n-Pr CF₃CH₂— CF₃CH₂— Me C 649 Me Me CF₃CH₂— CF₃CH₂— Me N 650 Me Et CF₃CH₂— CF₃CH₂— Me N 651 Me n-Pr CF₃CH₂— CF₃CH₂— Me N 652 Me i-Pr CF₃CH₂— CF₃CH₂— Me N 653 Me n-Bu CF₃CH₂— CF₃CH₂— Me N 654 Et Et CF₃CH₂— CF₃CH₂— Me N 655 Et n-Pr CF₃CH₂— CF₃CH₂— Me N 656 Et i-Pr CF₃CH₂— CF₃CH₂— Me N 657 Et n-B.u CF₃CH₂— CF₃CH₂— Me N 658 n-Pr n-Pr CF₃CH₂— CF₃CH₂— Me N 659 H Me Me CF₃CH₂— Me C 660 H Et Me CF₃CH₂— Me C 661 H n-Pr Me CF₃CH₂— Me C 662 H i-Pr Me CF₃CH₂— Me C 663 H n-Bu Me CF₃CH₂— Me C 664 H Me Me CF₃CH₂— Me N 665 H Et Me CF₃CH₂— Me N 666 H n-Pr Me CF₃CH₂— Me N 667 H i-Pr Me CF₃CH₂— Me N 668 H n-Bu Me CF₃CH₂— Me N 669 Me Me Me CF₃CH₂— Me C 670 Me Et Me CF₃CH₂— Me C 671 Me n-Pr Me CF₃CH₂— Me C 672 Me i-Pr Me CF₃CH₂— Me C 673 Me n-Bu Me CF₃CH₂— Me C 674 Et Et Me CF₃CH₂— Me C 675 Et n-Pr Me CF₃CH₂— Me C 676 Et i-Pr Me CF₃CH₂— Me C 677 Et n-Bu Me CF₃CH₂— Me C 678 n-Pr n-Pr Me CF₃CH₂— Me C 679 Me Me Me CF₃CH₂— Me N 680 Me Et Me CF₃CH₂— Me N 681 Me n-Pr Me CF₃CH₂— Me N 682 Me i-Pr Me CF₃CH₂— Me N 683 Me n-Bu Me CF₃CH₂— Me N 684 Et Et Me CF₃CH₂— Me N 685 Et n-Pr Me CF₃CH₂— Me N 686 Et i-Pr Me CF₃CH₂— Me N 687 Et n-Bu Me CF₃CH₂— Me N 688 n-Pr n-Pr Me CF₃CH₂— Me N 689 H Me CF₃CH₂— H Me C 690 H Et CF₃CH₂— H Me C 691 H n-Pr CF₃CH₂— H Me C 692 H i-Pr CF₃CH₂— H Me C 693 H n-Bu CF₃CH₂— H Me C 694 H Me CF₃CH₂— H Me N 695 H Et CF₃CH₂— H Me N 696 H n-Pr CF₃CH₂— H Me N 697 H i-Pr CF₃CH₂— H Me N 698 H n-Bu CF₃CH₂— H Me N 699 Me Me CF₃CH₂— H Me C 700 Me Et CF₃CH₂— H Me C 701 Me n-Pr CF₃CH₂— H Me C 702 Me i-Pr CF₃CH₂— H Me C 703 Me n-Bu CF₃CH₂— H Me C 704 Et Et CF₃CH₂— H Me C 705 Et n-Pr CF₃CH₂— H Me C 706 Et i-Pr CF₃CH₂— H Me C 707 Et n-Bu CF₃CH₂— H Me C 708 n-Pr n-Pr CF₃CH₂— H Me C 709 Me Me CF₃CH₂— H Me N 710 Me Et CF₃CH₂— H Me N 711 Me n-Pr CF₃CH₂— H Me N 712 Me i-Pr CF₃CH₂— H Me N 713 Me n-Bu CF₃CH₂— H Me N 714 Et Et CF₃CH₂— H Me N 715 Et n-Pr CF₃CH₂— H Me N 716 Et i-Pr CF₃CH₂— H Me N 717 Et n-Bu CF₃CH₂— H Me N 718 n-Pr n-Pr CF₃CH₂— H Me N 719 H Me H H Me C 720 H Et H H Me C 721 H n-Pr H H Me C 722 H i-Pr H H Me C 723 H n-Bu H H Me C 724 H Me H H Me N 725 H Et H H Me N 726 H n-Pr H H Me N 727 H i-Pr H H Me N 728 H n-Bu H H Me N 729 Me Me H H Me C 730 Me Et H H Me C 731 Me n-Pr H H Me C 732 Me i-Pr H H Me C 733 Me n-Bu H H Me C 734 Et Et H H Me C 735 Et n-Pr H H Me C 736 Et i-Pr H H Me C 737 Et n-Bu H H Me C 738 n-Pr n-Pr H H Me C 739 Me Me H H Me N 740 Me Et H H Me N 741 Me n-Pr H H Me N 742 Me i-Pr H H Me N 743 Me n-Bu H H Me N 744 Et Et H H Me N 745 Et n-Pr H H Me N 746 Et i-Pr H H Me N 747 Et n-Bu H H Me N 748 n-Pr n-Pr H H Me N 749 H Ph CF₃CH₂— CF₃CH₂— Me C 750 H Ph H CF₃CH₂— Me C 751 H Ph Me CF₃CH₂— Me C 752 H Ph H H Me C 753 H Ph CF₃CH₂— CF₃CH₂— Me N 754 H Ph Me CF₃CH₂— Me N 755 H Ph H CF₃CH₂— Me N 756 H Ph H H Me N 757 Me Ph CF₃CH₂— CF₃CH₂— Me C 758 Me Ph Me CF₃CH₂— Me C 759 Me Ph H CF₃CH₂— Me C 760 Me Ph H H Me C 761 Me Ph CF₃CH₂— CF₃CH₂— Me N 762 Me Ph Me CF₃CH₂— Me N 763 Me Ph H CF₃CH₂— Me N 764 Me Ph H H Me N

Methods for preparing the compounds of the present invention will be explained below. Among the compounds represented by the general formula (I), the compounds wherein R³ and R⁴ are a C₁-C₆ alkyl group or an ethyl group substituted with one or more halogen atoms can be prepared, for example, according to Reaction Route (1) or (2) set out below

In the above scheme, R¹, R², R⁵, and X have the same meanings as those defined above, and R⁶ represents a C₁-C₄ alkyl group or an ethyl group substituted with one or more halogen atoms. “W” represents a leaving group such as a halogen atom, p-toluenesulfonyloxy group, methanesulfonyloxy group, or trifluoromethanesulfonyloxy group.

A compound of the above general formula (II) and a compound of the above general formula (III) are first allowed to react with each other at a temperature of 10-250° C., preferably 130-180° C. for 0.1-20 hours, preferably 3-6 hours. A compound of the above general formula (IV) obtained by the above reaction can be separated and purified according to an ordinary means for separation and purification such as distillation, adsorption or partition chromatography, if necessary. The compound of the above general formula (IV) can be used for the next step after separation and purification as explained above, or alternatively, the product may be subjected to the following reaction without purification.

The compound of the above general formula (IV) is then allowed to react with a compound of the above general formula (V) at a temperature of 10-200° C., preferably 50-150° C. for 0.1-100 hours, preferably 5-20 hours in a suitable solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, triethylamine, or diazabicycloundecene to obtain a compound of the above general formula (I′).

Sources of the compound of the above general formula (II) as the starting material for Reaction Route (1), the compound of the above general formula (III), and the compound of the above general formula (IV) are not particularly limited. Those commercially available as reagents can be used, or those synthesized by a method known, per se, can also be used. A compound of the general formula (V) can be obtained by heating a compound of the general formula(VI) and a compound of the general formula (VIII), which are mentioned later, at a temperature of 50-100° C. in a suitable solvent such as acetonitrile or dimethyl sulfoxide.

The compound of the above general formula (I′) can also be prepared by the method set out below.

In the above general formulas R¹, R², R⁵, R⁶, X, and W have the same meanings as those defined above.

The compound of the above general formula (IV) obtained in Reaction Route (1) and a compound of the above general formula (VI) are allowed to react with each other at a temperature of 10-200° C., preferably 50-150° C. for 0.1-100 hours, preferably 5-20 hours in a suitable solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, triethylamine, or diazabicycloundecene to obtain a compound of the above general formula (VII).

The compound of the above general formula (VII) can be allowed to react with an amine represented by the above general formula (VIII) or hydrochloride thereof at a temperature of 10-200° C., preferably 70-120° C. for 0.1-100 hours, preferably 5-12 hours in a suitable solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone optionally in the presence of a suitable tertiary amine to obtain a compound of the above general formula (I′). The compound of the above general formula (I′) corresponds to a compound of the general formula (I) wherein each of R³ and R⁴ is a C₁-C₆ alkyl group or an ethyl group substituted with one or more halogen atoms.

Sources of the compound of the above general formula (VI) as the starting material for Reaction Route (2) are not particularly limited. Those commercially available as reagents may be used, or those synthesized by a method known per se may also be used.

The compound of the general formula (I′) is further reacted to obtain a compound of the general formula (I) having a substituent other than R⁶ of the compound of the general formula (I′).

A compound of the general formula (1) wherein R³ and R⁴ are hydrogen atoms can be obtained by hydrolyzing the compound of the above general formula (I′).

A compound of the general formula (I) wherein R³ is hydrogen atom, a C₁-C₆ alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms, and R⁴ is a C₁-C₆ alkyl group or an ethyl group substituted with one or more halogen atoms can be prepared by reacting the compound of the above general formula (I′) with a compound of the general formula R⁷OH (IX) wherein R⁷ represents hydrogen atom, a C₁-C₄ alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms at a temperature of 10-100° C., preferably 20-30° C. for 0.1-100 hours, preferably 5-12 hours without solvent or in a suitable solvent, for example, chlorine-containing solvent such as dichloromethane, pyridine, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone, and optionally in the presence of an acid such as p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, or phosphoric acid.

The compounds of the general formula (I) wherein R³ and R⁴ each independently represent hydrogen atom, a C₁-C₆ alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms can be obtained according to the method set out below.

In the above general formulas, R¹, R², R⁵, and X have the same meanings as those defined above, and R⁸ and R⁹ each independently represent a C₁-C₄ alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms.

A compound of the above general formula (I″) is first reacted with trimethylsilyldiethylamine at a temperature around room temperature for about one hour in a suitable solvent, for example, a chlorine-containing solvent such as dichloromethane, dichloroethane, or chloroform. For this reaction, 2 moles or more of trimethylsilyldiethylamine should be used per 1 mole of the compound of the above general formula (I″). Then, the reaction mixture is concentrated to dryness, and the resulting residue is dissolved in a suitable solvent, for example, a chlorine-containing solvent such as dichloromethane. To this solution, 2 moles or more of oxalyl chloride per 1 mole of the compound of above general formula (I″) is added, and the mixture is allowed to react for about 1 hour under ice cooling and then for about 1 hour at room temperature in the presence of catalytic amount of dimethylformamide.

After evaporating the solvent, the resulting compound of the above general formula (X), usually without further purification, is allowed to react with a compound of the general formula (XI) and/or a compound of the general formula (XII) at a temperature of 10-100° C., preferably 20-30° C. for 0.1-100 hours, preferably 5-12 hours in a suitable solvent such as chlorine-containing solvent such as dichloromethane, pyridine, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide and methylpyrrolidone. The resulting compound of the general formula (XIII) corresponds to a compound of the general formula (I) wherein each of R³ and R⁴ independently represents hydrogen atom, a C₁-C₄ alkyl group, an acylthioethyl group, or an ethyl group substituted with one or more halogen atoms.

The compounds of the above general formula (I″) used as the starting material for the above reaction can be obtained by hydrolyzing compounds of general formula (I′), as already explained above, or they can be efficiently obtained by preparing compounds of the above general formula (I′) from compounds of the above general formula (IV) wherein R⁶ is a C₁-C₄ alkyl group, and then reacting the resulting product with triethyliodosilane, trimethylbromosilane or the like.

A compound of general formula (I) wherein each of R³ and R⁴ is an acyloxymethyl group can be obtained by reacting a compound of the general formula (I″) with an acyloxymethyl halide represented by the general formula: R¹⁰Y (XIV) wherein R¹⁰ represents an acyloxymethyl group, and Y represents chlorine atom, bromine atom or iodine atom, at a temperature of 0-200° C., preferably 10-100° C. for 1-300 hours, preferably 10-200 hours in a suitable solvent such as acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or methylpyrrolidone in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, triethylamine, pyridine, diazabicycloundecene, or N,N′-dicyclohexyl-4-morpholinecarboxamidine.

The compound of the above general formula (I) obtained as described above can be separated from a reaction mixture and purified, if necessary, by applying an ordinary method for separation and purification of a nucleotide compound which can be suitably chosen from, for example, recrystallization, adsorption chromatography, ion exchange chromatography, partition chromatography and the like.

The compounds of the present invention have antiviral activity, as demonstrated in the test examples described later, and are expected to have antitumor activity in the same manner as other ionic phosphonate nucleotide analogues. Target viruses are not particularly limited. Specific examples include RNA viruses such as human immunodeficiency virus, influenza virus and hepatitis C virus, and DNA viruses such as herpes simplex virus I, herpes simplex virus II, cytomegalovirus, herpes zoster varicellosus virus, and hepatitis B virus, and a preferred example includes hepatitis B virus.

When the compound of the present invention or a pharmaceutically acceptable salt thereof, or a hydrate or a solvate thereof is used as medicaments, the substance, per se, can be administered, or administered as a pharmaceutical composition prepared in combination with a pharmaceutically acceptable carrier. A sort of the pharmaceutical composition can be decided depending on solubility and chemical properties of the substance, route of administration, dosage regimen and the like. For example, the pharmaceutical composition can be orally administered as a formulation such as, for example, granules, fine granules, powders, tablets, hard syrups, soft capsules, troches, syrups, emulsions, soft gelatin capsules, gels, pastes, suspensions, or liposome formulations, or administered intravenously, intramuscularly, or subcutaneously as an injection. The pharmaceutical composition may also be formulated as a powder for injection, and administered as an injection prepared upon use.

The pharmaceutically acceptable carriers include organic or inorganic solids or liquids for manufacturing pharmaceutical preparations suitable for oral, enteral, parenteral, or topical administration. Examples of the solid carriers for manufacturing solid pharmaceutical compositions include, for example, lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride and the like. Examples of the liquid carrier for manufacturing liquid pharmaceutical compositions for oral administration include glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, physiological saline, water and the like.

The pharmaceutical composition of the present invention may also contain auxiliaries other than the carrier mentioned above, for example, moistening agents, suspending aids, sweeteners, aromatics, colorants, preservatives and the like. Liquid pharmaceutical compositions may be encapsulated in capsules made of absorbable material such as gelatin and administered as capsules. Solvent or suspending medium used for the preparation of pharmaceutical compositions for parenteral administration, i.e., injection or the like, may be, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin or the like.

The compounds of the present invention, in particular, ester derivatives represented by the above general formula (I′) have high oral absorbability, as demonstrated in the test examples described later, and accordingly, pharmaceutical compositions for oral administration are preferred compositions among the pharmaceutical compositions of the present invention. The aforementioned pharmaceutical compositions can be prepared according to ordinary and conventional methods.

Dose may generally be within the range of 1-500 mg/kg, preferably 5-50 mg/kg for an adult based on the compound of the present invention as an active ingredient, when the medicament is administered orally. However, the dose may be appropriately increased or decreased for an administration depending on, for example, age, symptoms, and conditions of a patient, or a use or no use of other drug administered in combination. The aforementioned daily dose may be administered once a day, or the dose may be divided into two or several portions and administered with appropriate intervals. In addition, an administration can be performed intermittently. When used as injection, daily dose may generally be within the range of 0.1-50 mg/kg, preferably 0.1-5 mg/kg for an adult based the compound of the present invention as an active ingredient.

EXAMPLES

The present invention will be further explained more specifically by referring to the following examples. However, the scope of the present invention is not limited to the following examples.

Example 1

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl]-6-(dimethylamino)purine (Compound No. 11 in Table 1)

2-Chloroethyl chloromethyl ether (87 g, 670 mmol) and tris(2,2,2-trifluoroethyl)phosphite (200 g, 610 mmol) were allowed to react at 160° C. for seven hours to obtain 2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl chloride quantitatively.

The 2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl chloride (206 g) was dissolved in methyl ethyl ketone (2000 ml) and the solution was heated under reflux with sodium iodide (270 g) for eight hours. After the reaction was completed, the mixture was cooled to room temperature, and concentrated to dryness. The residue was dissolved in chloroform/hexane and adsorbed on a silica gel in a column, and then eluted with chloroform/hexane to obtain 2-[bis(2,2,2-trifluoroethyl) phosphonylmethoxy] ethyl iodide quantitatively.

2-Amino-6-(dimethylamino)purine (7.1 g, 40 mmol) was suspended in dimethyl sulfoxide (300 ml), and reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene (6.6 ml, 44 mmol) at 100° C. for one hour. Then, 2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl iodide (11.5 ml) was added to the reaction mixture, and the mixture was allowed to react at 100° C. for two hours. After the reaction was completed, the mixture was cooled to room temperature, and then concentrated to dryness. The residue was dissolved in chloroform and adsorbed on a silica gel in a column, and then eluted with 5%-methanol/chloroform to obtain the title compound (2.35 g, 12%) having the physicochemical properties set out below.

m.p.: 90-92° C. (diisopropyl ether); ¹H-NMR (CDCl₃, δ): 3.45 (s, 6H), 3.96-3.85 (m, 4H), 4.20-4.43 (m, 6H), 4.64 (s, 2H), 7.51 (s, 1H).

Example 2

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethy)phosphonylmethoxy]-ethyl]-6-(dimethylamino)purine (Compound No. 11 in Table 1)

2-Amino-6-chloropurine (15.0 g, 88 mmol) was suspended in dimethylformamide (360 ml), and reacted with 1,8-diazabicyclo[5.4.0]undec-7-ene (13.9 ml, 93 mmol) at 80° C. for one hour. Then, 2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl iodide (23.8 ml) was added to the reaction mixture, and the mixture was allowed to react at 100° C. for five hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform and adsorbed on a silica gel in a column, and eluted with 5%-methanol/chloroform to obtain 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonyl-methoxy]ethyl]-6-chloropurine (23.3 g, 56%).

Triethylamine (0.28 ml) and dimethylamine hydrochloride (0.16 g) were added to a solution of the 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-chloropurine (0.47 g, 1.0 mmol) obtained above in dimethylformamide (4.5 ml), and the mixture was stirred at 100° C. for five hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform and adsorbed on a silica gel in a column, and then eluted with 5%-methanol/chloroform to obtain 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-(dimethylamino)purine (0.33 g, 69%).

Example 3

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl]-6-(diethylamino)purine (Compound No. 16 in Table 1)

The title compound having the physicochemical properties set out below was obtained in the same manner as in Example 2, except that diethylamine was used instead of the dimethylamine hydrochloride.

m.p.: 105-106° C. (diusopropyl ether); ¹H-NMR (CDCl₃, δ): 1.24 (t, J=6.9 Hz, 6H), 3.80-4.10 (m, 6H), 4.20-4.48 (m, 6H), 4.54 (s, 2H), 7.51 (s, 1H).

Example 4

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl]-6-(1,1-dipropylamino)purine (Compound No. 20 in Table 1)

The title compound having the physicochemical properties set out below was obtained as syrup in the same manner as in Example 2, except that 1,1-dipropylamine was used instead of the dimethylamine hydrochloride.

¹H-NMR (CDCl₃, δ): 0.93 (t, J=7.4 Hz, 6H), 1.68 (tq, J=7.6 Hz, 4H), 3.60-4.10 (m, 8H), 4.17-4.50 (m, 6H), 4.60 (s, 2H), 7.49 (s, 1H).

Example 5

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl]-6-(methyl-1-propylamino)purine (Compound No. 13 in Table 1)

The title compound having the physicochemical properties set out below was obtained in the same manner as in Example 2, except that methyl-1-propylamine was used instead of the dimethylamine hydrochloride.

m.p.: 88-90° C. (diisopropyl ether); ¹H-NMR (CDCl₃, δ): 0.94 (t, J=7.4 Hz, 6H), 1.55-1.83 (m, 2H), 3.37 (bs, 3H), (m, 6H), 4.20-4.46 (m, 6H), 4.56 (s, 2H), 7.50 (s, 1H).

Example 6

Preparation of 2-amino-8-aza-9-[2-[bis(2,2,2-trifluoroethyl)phosphonyl-methoxy]ethyl]-6-(dimethylamino)purine (Compound No. 21 in Table 1)

The title compound having the physicochemical properties mentioned below was obtained in the same manner as in Example 1, except that 2-amino-8-aza-6-(dimethylamino)purine was used instead of the 2-amino-6-(dimethylamino)purine.

m.p.: 184-187° C. (chloroform); ¹H-NMR (DMSO-d₆, δ): 0.94 (t, J=7.4 Hz, 6H), 1.55-1.83 (m, 2H), 3.37 (bs, 3H), 3.80-4.10 (m, 6H), 4.20-4.46 (m, 6H), 4.56 (s, 2H), 7.50 (s, 1H).

Example 7

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl]-6-(benzylmethylamino)purine (Compound No. 129 in Table 1)

The title compound having the physicochemical properties set out below was obtained in the same manner as in Example 2, except that benzylmethylamine was used instead of the dimethylamine hydrochloride.

m.p.: 103-105° C. (diisopropyl ether); ¹H-NMR (DMSO-d₆, δ): 3.22 (bs, 3H), 3.85 (t, J=4.9 Hz, 2H), 4.03-4.16 (m, 4H), 4.53-4.80 (m, 4H), 5.22 (bs, 2H), 5.89 (s, 2H), 7.12-7.40 (m, 5H), 7.67 (s, 1H).

Example 8

Preparation of 2-amino-9-[2-[hexyl-(2,2,2-trifluoroethyl)phosphonyl-methoxy]ethyl]-6-(dimethylamino)purine

p-Toluenesulfonic acid (10 mg) was added to a solution of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-(dimethylamino)purine (0.96 g, 2.0 mmol) in 1-hexanol (5 ml), and the mixture was stirred at 110° C. for ten hours. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in chloroform and adsorbed on a silica gel in a column, and eluted with 1%-methanol/chloroform to obtain the title compound (771 mg, 80%).

¹H-NMR (CDCl₃, δ): 0.88 (t, J=6.6 Hz, 3H), 1.20-1.46 (m, 6H), 1.55-1.72 (m, 2H), 3.45 (s, 6H), 3.80-3.96 (m, involving d at 3.83, J=8.2 Hz, 4H), 4.00-4.16 (m, 2H), 4.18-4.46 (m, 4H), 4.61 (s, 2H), 7.54 (s, 1H).

Example 9

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]-ethyl]-6-(isopropylmethylamino)purine (Compound No. 14 in Table 1)

The title compound having the physicochemical properties set out below was obtained as oil in the same manner as in Example 2, except that isopropylmethylamine was used instead of the dimethylamine hydrochloride.

¹H-NMR (CDCl₃, δ): 1.24 (d, J=6.7 Hz, 6H), 3.21 (s, 3H), 3.88-4.02 (m, 4H), 4.17-4.50 (m, 6H), 4.57 (s, 2H), 7.51 (s, 1H).

Example 10

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonyl-methoxy]ethyl]-6-(methylphenylamino)purine (Compound No. 621 in Table 1)

The title compound having the physicochemical properties set out below was obtained in the same manner as in Example 1, except that 2-amino-6-(methyl phenylamino)purine was used instead of the 2-amino-6-(dimethylamino)purine.

m.p.: 147-152° C. (ethyl acetate, diisopropyl ether); ¹H-NMR (CDCl₃, δ): 3.78 (s, 3H), 3.86-3.96 (m, involving d at 3.91, J=7.8 Hz, 4H), 4.18-4.48 (m, 6H), 4.61 (s, 2H), 7.24-7,52 (m, 6H).

Example 11

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonyl-methoxy]ethyl]-6-(phenylamino)purine (Compound No. 613 in Table 1)

The title compound having the physicochemical properties set out below was obtained in the same manner as in Example 1 except that 2-amino-6-(phenylamino)purine was used instead of the 2-amino-6-(dimethylamino)purine.

m.p.: 126° C. (isopropanol); ¹H-NMR (CDCl₃, δ): 3.93-3.97 (m, 4H), 4.25-4.44 (m, 6H), 4.82 (s, 2H), 7.05-7,77 (m, 6H).

Example 12

Preparation of 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonyl-methoxy]propyl]-6-(phenylamino)purine (Compound No. 749 in Table 1)

The title compound having the physicochemical properties set out below was obtained as syrup in the same manner as in Example 1, except that 1-chloroisopropyl chloromethyl ether and 2-amino-6-(phenylamino)purine were used instead of the 2-chloroethyl chloromethyl ether and the 2-amino-6-(dimethylamino)purine.

m.p.: Syrup; ¹H-NMR (CDCl₃, δ): 1.26 (d, J=5.9 Hz, 3H), 3.76-3.88 (m, 1H), 3.90-4.10 (m, 3H), 4.16-4.24 (m, 1H), 4.30-4.46 (m, 4H), 4.79 (s, 2H), 7.07 (t, J=7.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 2H), 7.52 (s, 1H), 7.60 (s, 1H), 7.75 (d, J=7.6 Hz, 2H).

TEST EXAMPLE 1

Activity for inhibiting proliferation of Hepatitis B virus (HBV)

Inhibitory activity of the compounds of the present invention against proliferation of HBV was measured by a known method (K. Ueda, et al., VIROLOGY, 169, 213-216 (1989)).

2×10⁴ HB611 cells (recombinant human liver cancer cells producing HBV) were cultured in Dulbecco's ME medium containing 10% fetal bovine serum, streptomycin (100 μg/ml), penicillin (100 IU/ml), and Geneteicin (trade name of an antibiotic sold by Life Technologies, 0.2 mg/ml) at 37° C. The medium was changed with fresh medium on the second day and fifth day of the culture, and then changed with a medium containing a test compound at a final concentration of 10 μM or 1 μM on the 8th, 11th and 14th days of the culture. DNA of the cells were collected on the 17th day of the culture. Amounts of HBV-DNA in the cells were measured by Southern blotting method and inhibitory rates against HBV-DNA synthesis were determined. Concentrations of compounds required for 50% death of HB611 cells were determined by cell titer 96 (trademark of Promega Corp.). As references, the same test was carried out by using PMEA and its bis(pivaloyloxymethyl ester). The results are shown in Table 2 below. Compound Nos. in Table 2 correspond to those in Table 1.

TABLE 2 Inhibitory ratio against HBV - 50% Cytotoxic concen- Compound DNA synthesis (%) tration for HB611 No. 10 μM 1 μM cells (μM) 11 100 92 >1000 13 100 >1000 15 86.7 >1000 16 100 >1000 21 100 >1000 621 68 >1000 PMEA 83 334 PMEA ester¹ 90 63.7 18 ¹PMEA bis(pivaloyloxymethyl ester)

TEST EXAMPLE 2

Inhibitory effect on HBV proliferation in a serum of a rat orally administered with a test compound

A group consisting of three rats was orally administered with a test compound at a dose of 1 g/kg or 0.3 g/kg by a single oral administration. Blood of the rats was collected one hour after the administration and serum samples were prepared.

2×10⁴ HB611 cells were cultured in Dulbecco's ME medium containing 10% fetal bovine serum, streptomycin (100 μg/ml), penicillin (100 IU/ml) and Geneteicin (0.2 mg/ml) at 37° C. The medium was changed with fresh medium on the second day and fifth day of the culture, and then changed with a medium containing 5% of the above serum (the serum of the rat orally administered with a test compound) on the 8th, 11th and 14th days of the culture. DNA of the cells were collected on the 17th day of the culture. Amounts of HBV-DNA in the cells were measured by Southern blotting method, and inhibitory ratios against HPV-DNA synthesis in the cells were determined. As a reference, the same test was carried out by using PMEA. The results are shown in Table 3 below. Compound Nos. in Table 3 correspond to those in Table 1.

TABLE 3 Compound Dose of oral Inhibitory ratio against No. administration (g/kg) HBV-DNA synthesis (%) 11 0.3 95.6 13 0.3 100 PMEA 1 35.5

TEST EXAMPLE 3

Micronucleus test using mice

A test compound was administered to mice at a dose of 1,000 or 2,000 mg/kg, and bone marrow smear preparations were prepared at 24, 30, 48, and 72 hours after the administration. For a negative control group (0.5% aqueous solution of tragacanth gum) and a positive control group (2 mg/kg of mitomycin C (MMC) was administered as a single intraperitoneal administration), bone marrow smears were prepared at 24 hours after the administration. The samples were stained by the Giemsa's staining method in an ordinary manner, and then 2,000 polychromatic erythrocytes per animal were examined to determine the number of cells having micronuclei and frequency of appearance of micronuclei (%). As statistic analysis, significant difference test was carried out for polychromatic erythrocytes containing micronuclei between the negative control group and the group administered with a test compound according to the stochastic method of Kasternbaum and Bowman.

For comparison, the same test was carried out by using an unsubstituted 6-amino derivative, i.e., 9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-2,6-diaminopurine (abbreviated as “DAP”), and PMEA bis(pivaloyloxymethyl ester). The results are shown in Table 4 below. Compound Nos. in Table 4 correspond to those in Table 1.

TABLE 4 Compound No. Test result 11 Negative 13 Negative DAP Positive PMEA ester¹ Positive ¹PMEA bis(pivaloyloxymethyl ester)

INDUSTRIAL APPLICABILITY

The phosphonate nucleotide derivatives of the present invention have excellent antiviral activity and high oral absorbability. Therefore, they are expected to be useful as medicaments. 

What is claimed is:
 1. A phosphonate nucleotide derivative represented by the following general formula (I) or a salt thereof, or a hydrate or a solvate thereof:

wherein R¹ represents hydrogen atom, a C₁-C₆ alkyl group, or a C₇-C₁₀ aralkyl group; R² represents a C₁-C₆ alkyl group, a C₇-C₁₀ aralkyl group, or phenyl group; R³ and R⁴ independently represent an ethyl group substituted with one or more halogen atoms; R⁵ represents hydrogen atom, a C₁-C₄ alkyl group, a C₁-C₄ hydroxyalkyl group or a C₁-C₄ alkyl group substituted with one or more halogen atoms; and X represents —CH—.
 2. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein R¹ is hydrogen atom or a C₁-C₄ alkyl group; R² is a C₁-C₄ alkyl group, benzyl group, or phenyl group; and R⁵ is hydrogen atom or a C₁-C₄ alkyl group.
 3. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein R¹ is hydrogen atom or a C₁-C₄ alkyl group; R² is a C₁-C₄ alkyl group or phenyl group; and R⁵ is hydrogen atom or a C₁-C₄ alkyl group.
 4. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein R² is phenyl group.
 5. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein R¹ is hydrogen atom or a C₁-C₄ alkyl group; R² is phenyl group; and R⁵ is hydrogen atom or a C₁-C₄ alkyl group.
 6. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein R⁵ is a C₁-C₄ alkyl group.
 7. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein R¹ and R² are independently a C₁-C₄ alkyl group; and R⁵ is a C₁-C₄ alkyl group.
 8. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1, wherein said compound is selected from the group consisting of the following compounds: 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-(phenylamino)purine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]ethyl]-6-(N-methylphenylamino)purine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-(phenylamino)purine; 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-(N-methylphenylamino)purine; and 2-amino-9-[2-[bis(2,2,2-trifluoroethyl)phosphonylmethoxy]propyl]-6-(dimethylamino)purine.
 9. A pharmaceutical composition which comprises the compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1 together with a pharmaceutically acceptable carrier.
 10. A method for therapeutic treatment of a viral infectious disease which comprises the step of administering a therapeutically effective amount of the compound or the salt thereof, or the hydrate or the solvate thereof according to claim 1 to a patient with the viral disease.
 11. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 2, wherein R² is phenyl group.
 12. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 2, wherein R⁵ is a C₁-C₄ alkyl group.
 13. The compound or the salt thereof, or the hydrate or the solvate thereof according to claim 3, wherein R⁵ is a C₁-C₄ alkyl group. 